The present invention relates to a novel process for producing an optically active alcohol. More particularly, the invention relates to a novel process suitable for the practical production of an optically active xcex2-hydroxy acid compound useful as an intermediate for medicines or as a functional material, etc.
Conventionally known methods for synthesizing an optically active alcohol compound include 1) a method in which an enzyme such as a baker""s yeast is used and 2) a method in which a metal complex is used to asymmetrically hydrogenate a carbonyl compound. In particular, with respect to the latter method for asymmetric hydrogenation, many proposals have been made. Known examples thereof include: (1) a method in which a carbonyl compound having a functional group is asymmetrically hydrogenated in the presence of an optically active ruthenium complex catalyst (R. Noyori, Asymmetric Catalysis in Organic Synthesis, pp.56-82 (1994)); (2) a method in which a 1,3-dicarbonyl compound is asymmetrically hydrogenated with the aid of a ruthenium-diphosphine complex (Tetrahedron Asymmetry, Vol.8, pp.3327-3355 (1997)); (3) a method of asymmetric hydrogenation using a ruthenium-optically active phosphine complex (JP-B-6-99367) (the term xe2x80x9cJP-Bxe2x80x9d as used herein means an xe2x80x9cexamined Japanese patent publicationxe2x80x9d); (4) a method in which the hydrogen transfer reduction reaction of a carbonyl compound is utilized in the presence of an asymmetric complex catalyst comprising ruthenium, rhodium, or iridium (Chem. Rev., Vol.92, pp.1051-1069 (1992)); (5) a method in which a carbonyl compound is asymmetrically hydrogenated with the aid of a nickel complex modified with tartaric acid (Yu Kagaku, pp.828-831 (1980), and Y. Izumi, Advances in Catalysis, Vol.32, p.215 (1983)); (6) a method in which the asymmetric hydrosilylation reaction of a carbonyl compound is utilized (J. D. Morrison, Asymmetric Synthesis, Vol.5, Chap.4 (1985), and J. Organomet. Chem., Vol.346, pp.413-424 (1988)); (7) a method in which a carbonyl compound is reduced with a borane in the presence of an asymmetric ligand (J. Chem. Soc., Perkin Trans. I, pp.2039-2044 (1985), and J. Am. Chem. Soc., Vol.109, pp.5551-5553 (1987)); and (8) a method in which an acetophenone compound is asymmetrically hydrogenated in the presence of potassium hydroxide, an optically active diamine, and an asymmetric ruthenium complex catalyst (J. Am. Chem. Soc., Vol.117, pp.2675-2676 (1995)).
However, the above-described conventional methods for synthesizing an optically active alcohol have the following drawbacks. The synthesis method using an enzyme requires a complicated procedure and is restricted in substrates usable in the reaction. In addition, the alcohol compounds which can be obtained by the method are limited to those having a specific absolute configuration. On the other hand, the synthesis methods using a transition metal catalyst for asymmetric hydrogenation have problems that the rate of reaction is low and the optical purity of the optically active alcohol compound obtained by the asymmetric hydrogenation of a xcex2-keto ester compound is insufficient, although various transition metal complex catalysts have been reported.
Especially in the fields of medicines and functional materials, it is important to obtain an optically active alcohol compound having a specific absolute configuration and a high optical purity and it has hence been necessary to overcome the above-described problems of the conventional methods.
Accordingly, an object of the invention is to provide a novel process in which an optically active alcohol compound having a desired absolute configuration and a high optical purity can be obtained through the asymmetric hydrogenation of a xcex2-keto ester compound.
Under these circumstances, the present inventors made intensive investigations. As a result, it has been found that when a xcex2-keto ester compound is asymmetrically hydrogenated with the aid of a ruthenium metal complex having as a ligand an optically active [4,4xe2x80x2-bis-1,3-benzodioxol]-5,5xe2x80x2-diylbis(diphenylphosphine) (hereinafter also referred to as xe2x80x9cSEGPHOSxe2x80x9d simply), then the corresponding optically active alcohol having a high optical purity is obtained. As a result of further extensive studies by the present inventors, the invention has finally been completed.
The invention provides a process for producing an optically active alcohol represented by the following general formula (III): 
(wherein R1 represents a C1-C15 alkyl group which may have one or more substituents (selected from halogen atoms, a hydroxyl group, an amino group, amino groups protected by a protective group, amino groups substituted with one or more C1-C4 lower alkyl groups, amino groups protected by a mineral acid or organic acid, a benzyloxy group, C1-C4 lower alkoxy groups, C1-C4 lower alkoxycarbonyl groups, and aryl groups) or an aryl group; and R2 represents a C1-C8 lower alkyl group, or a benzyl group which may have one or more substituents)
which comprises asymmetrically hydrogenating a xcex2-keto ester compound represented by the following general formula (I): 
(wherein R1 and R2 are the same as defined above) in the presence of at least one ruthenium complex having as a ligand an optically active tertiary diphosphine compound represented by the following general formula (II): 
(wherein R3 and R4 each independently represent a cycloalkyl group, an unsubstituted or substituted phenyl group, or a five-membered heteroaromatic ring residue).
The invention further provides a process for producing the optically active alcohol which comprises conducting the asymmetric hydrogenation reaction in the presence of a specific ruthenium complex.
The invention furthermore provides a process for producing the optically active alcohol which comprises conducting the asymmetric hydrogenation reaction in the presence of a specific acid.
The invention will be explained below in detail.
Preferred examples of R1 in the xcex2-keto ester compound (I) for use as a starting material in producing the optically active alcohol by the process of the invention include C1-C15 alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, undecyl, dodecyl, and tridecyl; C1-C15 alkyl groups having one or more substituents (examples of the substituents include halogen atoms, hydroxyl, amino, amino groups protected by a protective group (e.g., acetyl, benzyloxycarbonyl, or t-butoxycarbonyl), amino groups protected by a mineral acid (e.g., hydrochloric acid, sulfuric acid, bromic acid, phosphoric acid, or hydriodic acid) or by an organic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, or acetic acid), amino groups substituted with one or more C1-C4 lower alkyl groups, C1-C4 lower alkoxy groups such as benzyloxy, methoxy, ethoxy, and t-butoxy, C1-C4 lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, and aryl groups such as phenyl, p-methoxyphenyl, p-tolyl, and 2-naphthyl), and aryl groups such as phenyl, p-methoxyphenyl, p-tolyl, and 2-naphthyl.
Preferred examples of R2 in the xcex2-keto ester compound (I) include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and octyl and a benzyl group which may have one or more substituents. Preferred examples of the substituents include methyl, ethyl, and methoxy.
Specific examples of the xcex2-keto ester compound (I) include methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, isopropyl acetoacetate, n-butyl acetoacetate, t-butyl acetoacetate, n-pentyl acetoacetate, n-hexyl acetoacetate, n-octyl acetoacetate, benzyl acetoacetate, methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, methyl 3-oxopentanoate, methyl 3-oxohexanoate, methyl 3-oxoheptanoate, methyl 6-methyl-3-oxoheptanoate, methyl 3-oxooctanoate, methyl 3-oxononanoate, methyl 3-oxodecanoate, methyl 3-oxoundecanoate, methyl 3-oxododecanoate, methyl 3-oxotridecanoate, methyl 3-oxotetradecanoate, methyl 3-oxopentadecanoate, methyl 3-oxohexadecanoate, methyl 3-oxoheptadecanoate, methyl 3-oxooctadecanoate, ethyl 3-oxopentanoate, ethyl 3-oxohexanoate, ethyl 3-oxoheptanoate, ethyl 3-oxooctanoate, ethyl 3-oxononanoate, ethyl 3-oxodecanoate, ethyl 3-oxoundecanoate, ethyl 3-oxododecanoate, ethyl 3-oxotridecanoate, ethyl 3-oxotetradecanoate, ethyl 3-oxopentadecanoate, ethyl 3-oxohexadecanoate, ethyl 3-oxoheptadecanoate, ethyl 3-oxooctadecanoate, methyl benzoylacetate, ethyl benzoylacetate, methyl 4-phenyl-3-oxobutanoate, methyl 4-benzyloxyacetoacetate, methyl 4-methoxyacetoacetate, dimethyl 3-oxooctanedioate, diethyl 3-oxooctanedioate, methyl 4-dimethylamino-3-oxobutanoate, ethyl 4-dimethylamino-3-oxobutanoate, methyl 4-amino-3-oxobutanoate hydrochloride, methyl 4-amino-3-oxobutanoate p-toluenesulfonate, methyl 4-amino-3-oxobutanoate methanesulfonate, 3-(ethoxycarbonyl)-2-oxopropyltrimethylammonium chloride, 3-(methoxycarbonyl)-2-oxopropyltrimethylammonium chloride, and methyl 4-benzyloxycarbonylamino-3-oxobutanoate.
The optically active tertiary diphosphine compound to be used in the invention is represented by the following general formula (II): 
(wherein R3 and R4 each independently represent a cycloalkyl group, an unsubstituted or substituted phenyl group, or a five-membered heteroaromatic ring residue). Preferred examples of the cycloalkyl groups represented by R3 and R4 include cyclopentyl, cyclohexyl, and cycloheptyl. Preferred examples of the five-membered heteroaromatic ring residues represented by R3 and R4 include 2-furyl, 3-furyl, 2-benzofuryl, and 3-benzofuryl. Examples of the substituents of the substituted phenyl groups include C1-C5 lower alkyl groups, C1-C5 lower alkoxy groups, di(lower alkyl)amino groups, and halogen atoms. The term xe2x80x9clower alkylxe2x80x9d as used herein means alkyl groups having 1 to 5 carbon atoms.
Preferred of the compounds represented by general formula (II) are compounds represented by formula (X): 
(wherein R5 and R6 each independently represent a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group, and R7 represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a di(C1-C4 alkyl)amino group).
More preferred are compounds represented by formula 
(wherein R8 and R9 are the same and each represent a hydrogen atom, t-butyl, n-butyl, n-propyl, isopropyl, ethyl, or methyl, and R10 represents a hydrogen atom, t-butoxy, isopropoxy, ethoxy, or methoxy).
The optically active tertiary diphosphine compound described above is known, and can be synthesized, for example, by the method described in JP-A-2000-16997 or JP-A-10-182678 corresponding to U.S. Pat. No. 5,872,273 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d).
The ruthenium complex to be used in the invention is a complex having the optically active tertiary diphosphine compound as a ligand, and is a known compound. Preferred examples of the complex are the following complexes represented by general formulae (IV) to (IX):
ruthenium-optically active tertiary phosphine complexes represented by:
[Ru2X4(L)2](A)xe2x80x83xe2x80x83(IV)
(wherein X represents a halogen atom, L represents an optically active tertiary phosphine ligand, and A represents a tertiary amine);
ruthenium-optically active tertiary diphosphine complexes represented by:
[RuX(arene)(L)]Xxe2x80x83xe2x80x83(V)
(wherein X and L are the same as defined above, and arene represents an optionally substituted benzene ring, preferred examples of which include benzene, toluene, xylene, cumene, p-cymene, ethylbenzene, and anisole);
ruthenium-optically active tertiary diphosphine complexes represented by:
[Ru(G)2(L)]xe2x80x83xe2x80x83(VI)
(wherein L is the same as defined above, and G represents a halogen atom or an acetoxy group);
ruthenium-optically active tertiary diphosphine complexes represented by:
[Ru(L)](J)2xe2x80x83xe2x80x83(VII)
(wherein L is the same as defined above, and J represents BF4, ClO4, PF6, or BPh4 (wherein Ph represents a phenyl group));
ruthenium-optically active tertiary diphosphine complexes represented by:
[{RuX(L)}2(xcexc-X)3][NH2Q2]xe2x80x83xe2x80x83(VIII)
(wherein L and X are the same as defined above, and Q represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, or cyclohexyl, a phenyl group which may have one or more substituents, or a benzyl group which may have one or more substituents) (preferred examples of substituents of the phenyl group include methyl, ethyl, methoxy, and ethoxy, and examples of the benzyl group which may have one or more substituents include 1-phenethyl); and
ruthenium-optically active tertiary diphosphine complexes represented by:
RuX2(L)(DMF)nxe2x80x83xe2x80x83(IX)
(wherein X and L are the same as defined above, n is an integer of 1 to 3, and DMF represents N,N-dimethylformamide).
Preferred examples of the complexes described above include the following.
[Ru2Cl4(SEGPHOS)2](NEt3)
[xe2x80x9cSEGPHOSxe2x80x9d means [4,4xe2x80x2-bis-1,3-benzodioxol]-5,5xe2x80x2-diylbis(diphenylphosphine)]
[Ru2Cl4(p-Tol-SEGPHOS)2](NEt3)
[xe2x80x9cp-Tol-SEGPHOSxe2x80x9d means [4,4xe2x80x2-bis-1,3-benzodioxol]-5,5xe2x80x2-diylbis(di-p-tolylphosphine)]
[Ru2Cl4(DM-SEGPHOS)2](NEt3)
[xe2x80x9cDM-SEGPHOSxe2x80x9d means [4,4xe2x80x2-bis-1,3-benzodioxol]-5,5xe2x80x2-diylbis(di-3,5-dimethylphenylphosphine)]
[RuCl(C6H6)(SEGPHOS)]Cl
[RuBr(C6H6)(SEGPHOS)]Br
[RuI(C6H6)(SEGPHOS)]I
[RuCl(p-cymene)(SEGPHOS)]Cl
[RuBr(p-cymene)(SEGPHOS)]Br
[RuI(p-cymene)(SEGPHOS)]I
[RuCl(C6H6)(p-Tol-SEGPHOS)]Cl
[RuBr(C6H6)(p-Tol-SEGPHOS)]Br
[RuI(C6H6)(p-Tol-SEGPHOS)]I
[RuCl(p-cymene)(p-Tol-SEGPHOS)]Cl
[RuBr(p-cymene)(p-Tol-SEGPHOS)]Br
[RuI(p-cymene)(p-Tol-SEGPHOS)]I
[RuCl(C6H6)(DM-SEGPHOS)]Cl
[RuBr(C6H6)(DM-SEGPHOS)]Br
[RuI(C6H6)(DM-SEGPHOS)]I
[RuCl(p-cymene)(DM-SEGPHOS)]Cl
[RuBr(p-cymene)(DM-SEGPHOS)]Br
[RuI(p-cymene)(DM-SEGPHOS)]I
[Ru(OAc)2 (SEGPHOS)]
[xe2x80x9cOAcxe2x80x9d represents an acetoxy group]
[Ru(OAc)2(p-Tol-SEGPHOS)]
[Ru(OAc)2(DM-SEGPHOS)]
[RuBr2(SEGPHOS)]
[RuBr2(p-Tol-SEGPHOS)]
[RuBr2(DM-SEGPHOS)]
[Ru(SEGPHOS)](BF4)2 
[Ru(SEGPHOS)](ClO4)2 
[Ru(SEGPHOS)](PF6)2 
[Ru(p-Tol-SEGPHOS)](BF4)2 
[Ru(p-Tol-SEGPHOS)](ClO4)2 
[Ru(p-Tol-SEGPHOS)](PF6)2 
[Ru(DM-SEGPHOS)](BF4)2 
[Ru(DM-SEGPHOS)](ClO4)2 
[Ru (DM-SEGPHOS)](PF6)2 
[{RuCl(SEGPHOS)}2(xcexc-Cl)3][NH2Me2]
[{RuCl(SEGPHOS)}2(xcexc-Cl)3][NH2Et2]
[{RuCl(p-Tol-SEGPHOS)}2(xcexc-Cl)3][NH2Me2]
[{RuCl(p-Tol-SEGPHOS)}2(xcexc-Cl)3][NH2Et2]
[{RuCl(DM-SEGPHOS)}2(xcexc-Cl)3][NH2Me2]
[{(RuCl(DM-SEGPHOS)}2(xcexc-Cl)3][NH2Et2]
[xe2x80x9cMexe2x80x9d represents a methyl group and xe2x80x9cEtxe2x80x9d represents an ethyl group]
RUCl2(SEGPHOS)(DMF)n 
RuCl2(p-Tol-SEGPHOS)(DMF)n 
RuCl2(DM-SEGPHOS)(DMF)n 
[xe2x80x9cDMFxe2x80x9d represents N,N-dimethylformamide]
The complexes shown above can be prepared, for example, by the method described in JP-A-10-182678 or JP-A-11-269185.
The process of the invention for preparing an optically active alcohol will be explained below. The xcex2-keto ester compound (I) described above, as a starting material, is asymmetrically hydrogenated in a solvent in the presence of the ruthenium complex, whereby an optically active alcohol can be prepared. Preferred examples of the solvent include protic solvents such as methanol, ethanol, and isopropyl alcohol. Also preferred is a mixed solvent composed of one or more such protic solvents and one or more of other solvents such as tetrahydrofuran, toluene, benzene, methyl acetate, ethyl acetate, methylene chloride, and the like. It is more preferred that the xcex2-keto ester compound (I) be dissolved in the solvent before being subjected to asymmetric hydrogenation reaction.
In order for the asymmetric hydrogenation reaction to proceed satisfactorily, the ruthenium complex is added to the solvent in an amount of preferably from 1/100 to 1/100,000 mol, more preferably from 1/1,000 to 1/50,000 mol, per mol of the xcex2-keto ester compound. This asymmetric hydrogenation reaction is generally conducted for from 1 to 48 hours with stirring under the conditions of a hydrogen pressure of from 0.1 to 10 MPa, preferably from 1 to 5 MPa, and a temperature of from 0 to 150xc2x0 C., preferably from 20 to 100xc2x0 C.
In the invention, the selectivity and conversion of the xcex2-keto ester compound as a starting material can be improved by conducting the asymmetric hydrogenation reaction in the presence of an acid. Preferred examples of the acid include mineral acids such as sulfuric acid and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid. In this case, such an acid is added in an amount of generally from 0.5 to 10 mole equivalents, preferably from 0.7 to 8 mole equivalents, more preferably from 0.9 to 5 mole equivalents, to the ruthenium complex.
After completion of the asymmetric hydrogenation reaction, the hydrogenation product may be purified in an ordinary manner. Usable purification techniques include a method in which the solvent is removed by distillation and the resulting residue is distilled under reduced pressure, a method in which the hydrogenation product is purified by silica gel column chromatography, and a method in which the hydrogenation product is purified by recrystallization.
The optically active alcohol (III) obtained by the process of the invention will be explained below. The optically active alcohol (III) corresponds to the xcex2-keto ester compound used as a starting material. This is because the keto group of the xcex2-keto ester compound is reduced to a hydroxyl group to give the optically active alcohol (III). Furthermore, either of the (R) isomer and the (S) isomer of the optically active alcohol can be obtained according to the selection of the ruthenium complex.
More specifically, different ruthenium complexes behave in the manners shown by the following scheme 1. 
It has therefore become possible to freely prepare the optically active alcohol having the desired absolute configuration by selecting a ruthenium complex.
Examples of the optically active alcohol include methyl 3-hydroxybutanoate, ethyl 3-hydroxybutanoate, octyl 3-hydroxybutanoate, benzyl 3-hydroxybutanoate, ethyl 4-chloro-3-hydroxybutanoate, ethyl 6-methyl-3-hydroxyheptanoate, methyl 3-hydroxytetradecanoate, ethyl 4-phenyl-3-hydroxybutanoate, ethyl 3-phenyl-3-hydroxypropionate, and ethyl 4-N-benzyloxycarbonylamino-3-hydroxybutanoate, which all are optically active.
According to the invention, it has become possible to produce an optically active alcohol by the practical process. Namely, the invention has made it possible to efficiently produce through a simple operation an optically active alcohol having a high optical purity and a specific absolute configuration. Because of this, optically active alcohols useful as intermediates for medicines or as functional materials, etc. have become easily producible. Furthermore, by conducting the reaction in the presence of a specific acid, selectivity can be greatly improved while keeping the high optical purity almost unchanged.
The invention will be explained below in more detail by reference to Examples, but the invention should not be construed as being limited to these Examples in any way. The optically active tertiary diphosphine compound used in the invention was synthesized by the method described in JP-A-2000-16997 or JP-A-10-182678. The ruthenium-optically active tertiary diphosphine complexes used were prepared by the method described in JP-A-10-182678.
Among the xcex2-keto ester compounds used in the invention, ethyl 4-benzyloxyacetoacetate was synthesized by the method described in JP-A-6-6522, while methyl benzoylacetate, dimethyl 3-oxooctanedioate, methyl 3-oxooctadecanoate, methyl 3-oxotetradecanoate, methyl 6-methyl-3-oxoheptanoate, and methyl 4-phenyl-3-oxobutanoate were synthesized by the methods described in Yuji Oikawa et al., J. Org. Chem., Vol.43, pp.2087-2088 (1978) and Heinz Thoma et al., Liebigs Ann. Chem., pp.1237-1248. Furthermore, methyl 4-amino-3-oxobutanoate hydrochloride was synthesized by the method described in JP-A-11-286479.
The following analytical instruments or means were used.
Determination of Asymmetric Yield
High-performance liquid chromatograph HPLC:
Waters 2690 (manufactured by Waters Inc.)
Detector, Waters 996 (manufactured by Waters Inc.)
Gas Chromatograph:
HP5890 series (manufactured by Hewlett Packard Co.)
Determination of Selectivity
Gas Chromatograph:
HP5890 series (manufactured by Hewlett Packard Co.)